Many current medicines suffer from poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches often fail to address the underlying ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid drug clearance is frequent or high dosing to attain a sufficiently high plasma level of drug. This, however, introduces a number of potential treatment problems such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment. A rapidly metabolized drug may also expose patients to undesirable toxic or reactive metabolites.
Another ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites. As a result, some patients receiving the drug may experience toxicities, or the safe dosing of such drugs may be limited such that patients receive a suboptimal amount of the active agent. In certain cases, modifying dosing intervals or formulation approaches can help to reduce clinical adverse effects, but often the formation of such undesirable metabolites is intrinsic to the metabolism of the compound.
In some select cases, a metabolic inhibitor will be co-administered with a drug that is cleared too rapidly. Such is the case with the protease inhibitor class of drugs that are used to treat HIV infection. The FDA recommends that these drugs be co-dosed with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism (see Kempf, D. J. et al., Antimicrobial agents and chemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs. Similarly, the CYP2D6 inhibitor quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism of dextromethorphan in a treatment of pseudobulbar affect. Quinidine, however, has unwanted side effects that greatly limit its use in potential combination therapy (see Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67; and FDA label for quinidine.
In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy for decreasing drug clearance. The inhibition of a CYP enzyme's activity can affect the metabolism and clearance of other drugs metabolized by that same enzyme. CYP inhibition can cause other drugs to accumulate in the body to toxic levels.
A potentially attractive strategy for improving a drug's metabolic properties is deuterium modification. In this approach, one attempts to slow the CYP-mediated metabolism of a drug or to reduce the formation of undesirable metabolites by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability. At the same time, because the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.
Over the past 35 years, the effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., Blake, M I et al, J Pharm Sci, 1975, 64:367-91; Foster, A B, Adv Drug Res 1985, 14:1-40 (“Foster”); Kushner, D J et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, M B et al, Curr Opin Drug Discov Devel, 2006, 9:101-09 (“Fisher”)). The results have been variable and unpredictable. For some compounds deuteration caused decreased metabolic clearance in vivo. For others, there was no change in metabolism. Still others demonstrated increased metabolic clearance. The variability in deuterium effects has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism (see Foster at p. 35 and Fisher at p. 101).
The effects of deuterium modification on a drug's metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem. 1991, 34, 2871-76). Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug.
This invention relates to novel tetrahydronaphthalene derivatives, and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a selective T-type calcium channel blocker.
Mibefradil also known as (1S,2S)-2-(2-((3-(2-benzimidazolylpropyl) methylamino)ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl methoxyacetate dihydrochloride is a calcium channel blocker that is known to selectively and potently block the T-type calcium channel and, through a de-esterified metabolite, to also block the L-type calcium channel (Massie, B. M., Am J Cardiol., 1997, Nov. 6, 80(9A):23I-32I). The pharmacologic activity of the de-esterified metabolite is approximately 10% that of the parent.
Mibefradil has demonstrated strong blood pressure reducing effects in patients with mild, moderate and severe hypertension, with less peripheral edema effects than other calcium channel blockers (Lacourcière, Y. et al., Am J. Hypertens. 1997 February; 10(2):189-96;) and has proven effective at improving exercise tolerance and reducing ischemic episodes in patients with chronic stable angina (see Massie above). Mibefradil was approved by the FDA in 1997 for treatment of hypertension, angina and cardiac failure, then was voluntarily withdrawn in 1998 due to potent drug-drug interactions with other medications resulting largely from its strong CYP3A4/5 inhibition and potentially also due to PGP inhibition (Wandel, C. et al., Drug Metabolism and Disposition, 2000, 28(8): 895-898). Although the exact mechanism of CYP3A inhibition is not known, it has been suggested that it results from oxidation of the benzimidazole moiety of mibefradil (Fontan, E et al, Curr Drug Metab 2005, 6:413-43).
Mibefradil is known to undergo metabolism through two metabolic pathways: esterase-catalyzed hydrolysis of the ester side chain (producing an alcohol metabolite known as Ro 40-5966); and cytochrome P450 3A4-catalyzed oxidation. Plasma concentrations of the alcohol metabolite resulting from de-esterification increase during chronic dosing and exceed those of the parent mibefradil at doses of 100 mg. The pharmacologic effect of the metabolite is approximately 10% of that of the parent.
Mibefradil's and Ro-40-5966's CYP 3A4 metabolism occurs predominantly at two molecular sites, most prominently the benzylic site of the tetrahydronaphthalene, and also to a significant extent alpha to the tertiary amine leading to removal of the N-methyl or the propylbenzimidazole groups. CYP 3A4 catalyzed metabolism also occurs to a limited extent on the benzimidazole ring of mibefradil at both the 4- and 5-positions (Wiltshire, H. R. et al., Xenobiotica, 1997, 27(6): 539-556).
When administered intravenously to healthy male volunteers, mibefradil caused a dose-dependent increase in bilirubin in all cases, and a severe decrease in plasma haptoglobin in two cases (Kleinbloesem C. H. et al., Journal of Cardiovascular Pharmacology, 1995, 25(6): 855-858).
Despite the beneficial activities of mibefradil, there is a continuing need for new compounds to treat the aforementioned diseases and conditions.